Opioid Analgesics for Persistent Pain in the Older Patient: Part I
The opioid analgesics are among the oldest of drugs in use today, with evidence of use dating back thousands of years. These agents mimic the endogenous opioid peptides and act by reducing neuronal excitability (by hyperpolarizing the neuron via enhancement of potassium ion influx) and inhibiting neurotransmitter release (by reducing calcium ion influx). Their effects are mediated by binding to specific receptors in the central and peripheral nervous systems (Table I).1
In this two-part article, some general concepts underlying the use of opioid analgesics will be covered, and selected individual agents will be discussed. Part I will provide information on selected general concepts in opioid therapeutics, including the role of opioids in pain management, treatment of concurrent acute pain, toxicity, and drug-drug interactions. Part II, to be published in the next issue of the Journal, will discuss dosing of opioid analgesics, pharmacogenomics, and the individual agents. For the purpose of these articles, the term opioid will refer to all naturally-occurring, semisynthetic and synthetic agents and endogenous peptides that act by binding to one or more opioid receptor types in the body. Only those opioid analgesics available in the United States that are administered orally, transdermally, or transmucosally will be discussed (Table II).1 Emphasis will be placed on the chronic use of these agents in the older population for the treatment of persistent pain. The following opioid analgesics, which by general consensus should not be used in older individuals, will not be discussed: meperidine; the mixed agonist-antagonists pentazocine, nalbuphine, butorphanol; and the partial agonist buprenorphine. Propoxyphene will similarly not be discussed in light of the actions of a U.S. Food and Drug Administration (FDA) panel that voted 14-12 in early 2009 to recommend withdrawal of all propoxyphene-containing products from the U.S. marketplace. This agent, by general consensus, also should not be used in older individuals.
Selected General Concepts in Opioid Therapeutics
Role of Opioids in Pain Management
Opioid analgesics are an important drug class to consider for the control of moderate-to-severe pain. The paucity of guidelines for opioid use in older persons or discussion of elder-specific issues in general pain guidelines is a reflection of the paucity of studies of these agents in this patient population. However, a review of the evidence base had led to at least some preliminary recommendations for the use of opioids in older patients.2
Few high-quality data exist regarding opioid use in cancer-related pain in older persons. In general, sufficient high-quality data exist in non-elderly cancer populations to consider all opioids to be effective in geriatric cancer pain management, despite the lack of well-designed elder-specific studies.2,3 The need to maintain continuity of opioid dosing upon transfer across healthcare settings has been identified as a major potential concern in this population, especially if different opioid dose conversion charts and different formulary opioid products are used in the various settings.4
In musculoskeletal pain syndromes, a high-quality evidence base demonstrating the efficacy of opioids has been steadily growing. Again, few elder-specific data are available; however, it can be concluded that opioids are effective in these noncancer pain syndromes.2,3 The major controversy lies in the timing of initiation of opioid analgesia. In osteoarthritis, most authorities would consider opioids best restricted to circumstances in which acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs; including celecoxib), and the dual-mechanism (mu-opioid receptor agonist plus serotonin-norepinephrine reuptake inhibitor [SNRI]) compounds tramadol/tapentadol (as single agents or in combination with acetaminophen or NSAIDs) have failed or are contraindicated or poorly tolerated.5,6 In inflammatory musculoskeletal diseases, opioids are best used either at the time of diagnosis as adjuncts to anti-inflammatory drugs when initial inflammation is causing severe pain or at the end of the disease course when unremittingly painful secondary pathologic changes have occurred.5 With chronic low back pain, opioids are best used at the point where moderate-to-severe pain is still present despite maximal nonopioid drug management.5 In all of the musculoskeletal pain syndromes, the previous nonopioid regimen should be continued when opioid therapy is initiated, in order to keep the opioid dose as low as possible.6 The only exception to this may be the possible need to discontinue tramadol/tapentadol when the pure opioid agonist is started, due to the theoretical potential for induction of serotonin syndrome and the increased risk of seizures during concurrent therapy.6
Traditionally, neuropathic pain (eg, postherpetic neuralgia, painful diabetic neuropathy, phantom limb pain) has not been felt to be particularly responsive to opioids. However, better-designed studies and meta-analyses have clarified the role of opioids in the treatment of these common and debilitating pain syndromes. Opioids are not particularly beneficial when used on an “as-needed” basis for acute painful paroxysms.7 However, reasonably high-quality evidence does demonstrate a beneficial effect on chronic neuropathic pain.2,8-10 Neuropathic pain guidelines recommend their use as second-line or third-line therapy after use of monotherapy or combination therapies of topical lidocaine, the gabapentanoids gabapentin and pregabalin, tricyclic antidepressants (TCAs), and SNRIs (eg, venlafaxine, duloxetine). In this circumstance, the opioid is added to the existing regimen.9,10 Opioid therapy is not recommended in trigeminal neuralgia or central post-stroke pain.10 Combination opioid-gabapentanoid therapy frequently allows lower doses of both components to be used as compared with either as monotherapy, thus improving tolerability.11,12
Recently, the evidence for effectiveness of long-term opioid therapy ( 6 mo) in chronic noncancer pain states was reviewed. The evidence base for both efficacy in reducing pain and in improving functional status was quite variable across the opioid class. For example, long-term use of transdermal (TD) fentanyl, sustained- or extended-release (ER) morphine, and oxycodone were much better supported than was long-term use of hydrocodone and methadone.13
Treatment of Concurrent Acute Pain
Opioid recipients suffering from chronic pain who have an acute pain syndrome superimposed upon it (eg, major surgery, trauma) require additional analgesia in order to optimally manage both types of pain. The chronic pain component should be managed by either maintaining the previous opioid regimen or, if necessary, by switching to another opioid at 50-100% of the calculated equianalgesic dose (the latter concept will be covered in Part II of this article). The opioid dosing regimen for the acute pain component needs to be more aggressive than usual acute pain regimens, with scheduled and/or “as-needed” doses being increased and/or dosing intervals reduced. Dosage increments frequently range from 50-100% of usual acute pain dosages. The cumulative equianalgesic daily dosage of opioid for the management of acute pain in chronic opioid recipients usually ranges from 20-50% of the daily chronic pain regimen. A multimodal approach using other analgesics such as acetaminophen, NSAIDs, or regional anesthesia in addition to opioid therapy may be very useful in this challenging patient subpopulation.14
Effects of Older Age on Opioid Efficacy and Tolerability
A traditional teaching in geriatric pharmacology has been that older individuals are more resistant to opioid analgesia and are more sensitive to opioid adverse effects. In a recent systematic review and meta-analysis, the risk factors for poor versus good outcomes in patients with chronic noncancer pain treated with opioids were reviewed15 Younger—not older—age was a risk factor for subsequent opioid misuse/abuse. Older age was associated with an increased risk of respiratory depression but a decreased risk of nausea and vomiting. Younger, as compared with older, age predicted enhanced pain reduction and greater ratings of pain relief. However, these findings were not universal among the reviewed studies.15
Examining only those studies published within the past two years, the effects of advancing age on opioid analgesia and tolerability have been inconsistent. Pain response was reported to be unaltered as a function of age in two studies,16,17 while it was significantly enhanced in elderly as compared with young patients in two other studies.18,19 Study discontinuation rates due to lack of efficacy were not related to age in the studies by Peniston and Gould16 and Likar et al.19 In addition, the proportion of nights with “good” sleep and use of rescue analgesia were not related to age in the study by Likar et al.19 Adverse event (AE) types/frequencies were not related to age in two of the studies,16,19 and study discontinuation rates due to AEs were also not related to age in one of these studies.19 Reported AE rates were significantly lower in elderly as compared with young patients in a study by Gnjidic et al.2 The rate of excessive sedation was found to be independent of age in a study by Keita et al17 and significantly increased in elderly as compared with young patients in another study by Pesonen et al.18 Postoperative nausea was unrelated to age in the latter study.18 It appears that it is difficult to make any generalizations with regard to the efficacy and tolerability of opioid analgesics in the elderly as compared with the young.
The AEs of opioids serve as their “Achilles heel” in the eyes of most practitioners and patients. However, most of these AEs can be anticipated and, in some cases, proactively managed. In other cases, despite a lack of means of proactive management, they will disappear after a short period of time due to the development of tolerance. Tolerance generally occurs to all but the constipating and miotic effects of these agents.
Only 7-10% of opioid recipients experience persistent sedation. In such individuals, management involves either switching to a different opioid (first-line) or addition of a central nervous system (CNS) stimulant (second-line).
The potential for opioid therapy to impair motor vehicle operation by older individuals has largely been unexplored. In a study involving individuals stopped by police for suspected driving under the influence who also had methadone present in their blood specimens, no drug concentration-response (ie, impairment) relationship was noted.21 This was the case for the 10 individuals with methadone as the only psychoactive drug present, as well as the 625 persons with methadone plus at least one other psychoactive drug present. Numerous limitations preclude extrapolation to the elderly population (ie, the population was over 86% male and age 30-40 yr; the effect measured was all-or-none, reducing sensitivity; concurrent psychoactive drugs made interpretation of results problematic; in one-third of patients, multiple opioids were present in the blood specimens; too few persons were receiving methadone alone).21
Another area of great importance in the older population is the potential for opioids to exert negative effects on cognition and the ability to perform (instrumental) activities of daily living. Again, elder-specific data are lacking. In a recent systematic review of the cognitive effects of opioids in patients with cancer, six of ten studies reported a significant association between poor cognitive performance (reaction time, attention, balance, memory) and opioid use.22 Several limitations make it difficult to extrapolate these results to elderly opioid recipients, regardless of their cancer status: cognitive changes can occur due to cancer itself or its complications/consequences, making the distinction between drug- and disease-associated effects difficult to determine; and the clinical relevance of deficits identified by neuropsychometric testing are poorly understood. Other deficiencies included the following: small enrollment numbers; inadequate controls; few pre- versus post-measurements; short duration; lack of assessment of the effects of concurrent drugs, pain itself, and mood disorders; and lack of comparisons between opioids.22
In general, opioids appear to worsen performance during the first few days of use and over the initial few hours after each dose administration, especially with respect to timed performance on psychomotor tasks. Results become inconsistent when the duration of exposure exceeds 3 days. Few differences are noted when the performance of these “long-term” opioid recipients is compared with their own performance prior to initiation of opioid therapy or to that in a comparable pain population not receiving opioids. However, few data are available regarding differences between opioids, dose-response relationships, drug-drug interactions (DDIs), and variables affecting response (especially age). In addition, there are virtually no data in this regard in those with pre-existing cognitive impairment or diminished “cognitive reserve.”22
Nausea and vomiting occur due to stimulation of receptors within the chemoreceptor trigger zone in the area postrema of the medulla. Triggers involve input via the eighth cranial nerve and/or severe constipation. Minimization of movement; short-term use of metoclopramide, prochlorperazine or thiethylperazine, corticosteroids, and/or benzodiazepines; and/or aggressive laxative therapy can help until tolerance develops.
Constipation, a dose-dependent AE, is caused by multiple effects of opioids on the gastrointestinal (GI) tract (reduction in intestinal secretions, increase in intestinal fluid absorption, and reduction in propulsive motility). Few data are available to suggest that there is a clinically relevant difference between opioids in this regard. However, one recent meta-analysis involving four randomized, controlled clinical trials (N = 425 patients) did find a significant difference favoring TD opioids (fentanyl, buprenorphine [latter not available in the United States]) over long-acting morphine products (odds ratio, 0.38; P < 0.001). Caution in the interpretation of this meta-analysis is warranted, however, due to the small number of trials (N = 4), the heterogeneity occurring in some results, and the low quality of some trials.23
Because tolerance to this AE does not develop, an aggressive laxative program should be initiated at the time that opioid therapy is started. Unfortunately, many chronic opioid recipients are not provided proactive laxative therapy. For example, in a retrospective cohort study conducted in the province of Quebec, Canada, in 2005, only 15% of chronic opioid recipients had one or more laxatives prescribed concurrently.2 Generally, scheduled oral stimulant therapy (eg, senna or bisacodyl) dosed to the desired effect with “as-needed” oral osmotic (magnesium salt or sorbitol), rectal stimulant, and/or rectal osmotic (phosphate enema) orders is recommended.
Numerous attempts have been made to circumvent opioid-induced bowel dysfunction using concurrent administration of opioid receptor antagonists. Despite the poor oral bioavailability of naloxone, concurrent oral opioid-naloxone administration has produced antagonism of opioid analgesia and precipitation of opioid withdrawal signs/symptoms.2 This suggests that local and CNS opioid receptor blockade occurred with this combination of agents. Subcutaneous (SC) methylnaltrexone is now available for the treatment of opioid-induced bowel dysfunction.26-28 It is FDA-approved for the treatment of opioid-induced constipation in patients with advanced illness receiving palliative care when the response to laxative therapy has been insufficient. This agent reverses the effect of opioids on GI transit time and produces laxation within a short time period in a majority of subjects. It does not reverse opioid analgesia (ie, increase pain scores, increase opioid consumption) and does not precipitate opioid withdrawal. Common AEs include abdominal pain, gas, nausea, dizziness, and diarrhea. It is expensive and invasive, available only for SC administration currently. This agent has not been evaluated as a proactive treatment to prevent the development of constipation by maintaining regular stooling. It is currently used only to relieve intractable constipation in single doses. Also, there have been no studies comparing this agent to usual scheduled and “as-needed” pharmacological regimens. Its use should be restricted to those patients developing constipation who are unresponsive to maximal scheduled and “as-needed” laxative regimens.
Oral alvimopan is similar to SC methylnaltrexone in being a peripheral, and not central, opioid antagonist. It is FDA-approved for accelerating the time to upper and lower GI motility recovery following partial large- or small-bowel resection with primary anastomosis.29 It is contraindicated in patients using opioids for more than 7 consecutive days prior to its use.2 Few data are available for the indication of opioid-induced constipation. This is due, in part, to the results of a long-term (12 mo) safety study that found alvimopan 1 mg daily to be associated with an increased risk of cardiovascular AEs as compared with placebo in patients treated with opioids for chronic pain.29 These findings have been investigated for their clinical relevance and the potential consequences for the safety of this agent, especially in long-term use. The FDA has now lifted the hold on the clinical investigation program in opioid-induced constipation. The most common AEs in postoperative patients are anemia, dyspepsia, hypokalemia, back pain, and urinary retention ( 3% with alvimopan vs 1% with placebo).29
A less prevalent but problematic AE of opioids is neurotoxicity, which can manifest as cognitive impairment, delirium, severe sedation, hallucinations (tactile more so than visual), myoclonus, and seizures. Risk factors include high opioid doses, prolonged exposure, pre-existing borderline cognitive impairment, dehydration, renal disease, and concurrent use of opioid agonist-antagonists or other psychotropic drugs.30-32 Other potential findings include the development of abnormal pain symptoms such as allodynia (where normally innocuous stimuli such as bed covers or clothing produce severe pain) and hyperalgesia (reduction in the pain threshold, leading to the appearance of worsening pain despite typically rapidly accelerating opioid doses).31 Hyperalgesia is thought to be due to an opioid-induced imbalance between the internal antinociceptive system (mediated by endogenous opioids) and the pronociceptive system (mediated by N-methyl-D-aspartate [NMDA] receptor activation and cholecystokinin).31 Hyperalgesia develops independent of the reason for chronic opioid use.33 Whenever the clinician observes the development of apparent opioid tolerance, several potential etiologies must be evaluated. Is the increase in pain due to worsening of the pathophysiology producing the pain in the first place? Is it due to the appearance of true tolerance (a rare phenomenon)? Is the request for more analgesic the result of substance abuse (addiction)? Finally, is it due to drug-induced hyperalgesia? Administering one additional opioid dose can help to distinguish true opioid tolerance (ie, the pain will get better) and hyperalgesia (ie, the pain will get worse). Treatments for hyperalgesia include opioid dose reduction or an opioid switch (rotation) to another mu-opioid receptor agonist (especially methadone due to its NMDA receptor antagonist properties; perhaps to kappa-opioid receptor agonists such as the agonist-antagonists).31 Another treatment is the concurrent use of an NMDA receptor antagonist such as dextromethorphan or ketamine. However, the former agent has performed poorly in clinical trials while the latter agent has its own potentially serious AEs.31
Among the reviewed agents, tramadol has the greatest propensity to induce seizures, even after the initial dose. Seizure risk is increased by concomitant use of SSRIs, TCAs, cyclobenzaprine (and other tricyclic compounds), other opioids, neuroleptics, and other drugs lowering the seizure threshold. Risk is also increased in those with a past history of epilepsy, head trauma, and metabolic disorders, as well as those undergoing drug/ethanol withdrawal. In MedWatch reports, seizure types have been generalized tonic-clonic in 43%, nonspecific in 38.8%, and a miscellaneous collection of types in 18.2%. Drug overdose has been suggested in 24.2% of reports. Conflicting data have been obtained from observational case-control trials, in terms of quantifying the seizure risk. In the overall population, the risk appears to be less than 1%. Whether or not tapentadol is also associated with an enhanced seizure risk as compared with other opioids is not known.34-38 Tapentadol has greater abuse potential than tramadol, with the former being a schedule II controlled substance and the latter being nonscheduled under the Controlled Substances Act.39
Among the reviewed agents, tramadol and tapentadol are unique in the potential ability to induce serotonin syndrome, a life-threatening condition associated with an overabundance of serotonergic neurotransmission in the CNS. It is characterized by disorders of cognition/behavior (eg, delirium, psychosis, decreased level of consciousness), neuromuscular activity (eg, muscle rigidity, rhabdomyolysis), and autonomic dysfunction (eg, pyrexia, tachycardia, hypertension, diaphoresis). In most cases, serotonin syndrome emerges when multiple serotonergic drugs are being used concomitantly (eg, tramadol/tapentadol plus SSRIs, SNRIs, TCAs, triptans, monoamine oxidase inhibitors [MAOIs]). Drugs with MAOI activity, such as selegiline, rasagiline, furazolidone (no longer available in the United States), linezolid, and procarbazine, may also be problematic.34-37,40 However, there have also been documented cases of serotonin syndrome due to tramadol used alone.
All opioids are dose-dependent respiratory depressants, reducing respiratory rate, tidal volume, and response of the respiratory center to increasing pCO2. This is rarely an issue in chronic opioid recipients. Most frequently, respiratory depression occurs during short-term use of high-dose opioids in the initially opioid-naïve. Of interest, the risk of developing respiratory depression in this situation is age-dependent, with 2.8-, 5.4-, and 8.7-fold increased risks in persons age 61-70, 71-80, and older than 80 years, respectively, as compared with those age 16-45 years (all P < 0.05).41 Caution is mandated with the use of opioid antagonists in treating this, since the usual recommended doses will also reverse analgesia, resulting in an elevation in pain intensity, and precipitate withdrawal. Owing to the short terminal disposition half-life (t1/2) of naloxone (mean, 0.5 h), short-term continuous IV infusion administration may be necessary, especially with opioids with long t1/2’s, such as methadone (4-150 hr), TD fentanyl (16-24 hr), and levorphanol (12-16 hr).
Opioid receptors are located in the same nuclei that are active in sleep regulation, and opioid peptides may be involved in the induction and maintenance of the sleep state. Abnormalities of sleep architecture during opioid therapy are well known. During the initiation phase of chronic opioid therapy, rapid eye movement (REM) sleep, slow-wave sleep (SWS), total sleep time (TST), and sleep efficiency decrease, while wakefulness, arousals from sleep, and REM sleep latency increase. During the maintenance phase, the reductions in REM sleep and SWS and the increments in wakefulness, arousals from sleep, and REM sleep latency tend to normalize. However, vocalizations occurring during REM sleep, significant delta bursts, and daytime sleepiness become more common. During acute opioid abstinence, significant insomnia, frequent arousals from sleep, and reductions in REM sleep occur. During protracted abstinence, TST significantly increases while SWS and REM sleep rebound.42
Most studies of acute opioid use have not documented sleep-disordered breathing, although one study did demonstrate a doubling of apnea episodes (P = not significant [NS]) and a significant reduction in awake ventilatory response to hypoxia.42 With prolonged opioid use, 30-90% of individuals exhibit sleep apnea, especially central sleep apnea (CSA) or the combination of obstructive and CSA. Currently, CSA due to opioid therapy is felt to be due to changes in central and peripheral control mechanisms (ie, blunted central and enhanced peripheral chemosensitivities). It is not known whether CSA associated with opioid use has poorer outcomes than CSA associated with other etiologies.4 However, it has been hypothesized that sleep apnea may be a possible mechanism of the increased mortality noted in patients on chronic opioid therapy.43 It also appears that chronic opioid use is a risk factor for complex sleep apnea syndrome (ie, occurring in patients with obstructive sleep apnea who manifest respiratory control dysfunction and CSA while on continuous positive airway pressure).43 Whether or not a dose-response relationship exists between opioids and various indexes of sleep-disordered breathing is controversial.43,44 Whether or not daytime sleepiness and reduced daytime functioning are a result of opioid-associated sleep-disordered breathing is also controversial. In recipients of methadone maintenance therapy (MMT), it appears that there may be no relationship of either daytime outcome with opioid-associated sleep-disordered breathing.45 However, this does not mean that the same finding will be noted in the chronic pain population. Last, acetazolamide has been demonstrated to reverse CSA due to opioids.46 However, acetazolamide can be a difficult drug to use in the elderly due to its AEs and dependence on intact renal function for elimination.
High-dose opioids can precipitate male and female hypogonadotropic hypogonadism by suppressing gonadotropin release, and thus reducing free and total sex steroid concentrations. This may produce sexual dysfunction (decreased libido and erectile dysfunction), amenorrhea, oligomenorrhea, osteopenia/osteoporosis, and reduced energy and muscle strength.47-49 In patients with chronic noncancer pain who were taking oral opioids, the prevalence of hypogonadism was significantly higher in males as compared with females (75% and 21%, respectively; P < 0.01), while the prevalence of osteopenia was not significantly different (50% and 21%, respectively).5 In another study, bone mineral density (BMD) was quantitated in 81 males (age 20-84 yr; mean age, 45 yr) who received opioids on a chronic basis. Osteoporotic (8%)/osteopenic (36%) BMD values were found in 44% of participants, while BMD values were normal in the other 56%. Twenty-seven percent were hypogonadal (50% of hypogonadal males had BMD values in the osteoporotic [9%]/osteopenic [41%] range, while the other 50% had normal BMD values). Lastly, 42% of participants with total serum testosterone concentrations in the normal range had osteoporotic (8%)/osteopenic (34%) BMD values. Other risk factors for subnormal BMD values were not explored, which may account for the results obtained. At this time, serum testosterone concentration monitoring is not a reliable method to determine the risk of opioid-associated bone disease. The role of routine BMD screening in males receiving chronic opioid therapy is unclear at present.51
Opioids, in common with other CNS depressants, increase the risk of hip fractures in the elderly. A case-control study was conducted involving 4500 elders (elder defined as being 65 yr) with hip fractures (cases) and 24,041 age- and gender-matched controls. The relative risk (RR), as compared with controls, of current codeine or propoxyphene recipients was 1.6 (95% confidence interval [CI], 1.4-1.9). For new users (defined as initiating opioid within 90 days of the event), RR was 2.2 (95% CI, 1.7-2.8). Lastly, for current users of combinations of opioid and nonopioid psychotherapeutics, RR was 2.6 (95% CI, 2.0-3.4). All of these associations were statistically significant. The RR of hip fracture during combination therapy (2.6) was greater than that of both monotherapies (both being 1.6).52
Prescription opioid abuse in the older population is not a rare phenomenon. For example, the frequencies of Emergency Department visits due to the nonmedical use of opioids were 37, 82, 90, and 30 cases per 100,000 prescriptions in those age 12-20, 21-34, 35-54, and 55 years and older (12-20 vs 55 yr; P = NS).53 At present, the frequency of addiction due to the chronic use of therapeutic opioids is quite low. In a meta-analysis of 24 papers (N = 2507), the overall calculated addiction rate was 3.3%. In those preselected as having no previous or current history of abuse/addiction, this rate fell to 0.2%. In terms of aberrant drug-related behaviors (eg, requesting pain medications, unsanctioned dose elevations), the overall calculated aberrant behavior rate was 11.5% (17 papers; N = 2466). In the same subpopulation preselected as previously described, this rate fell to 0.6%.54 The “baby boomer” generation, a population in which there has been greater lifetime illicit drug use than in all previous generations, is poised to become the next generation of elders. Over the next 15-20 years, there will be an unprecedented number of older drug users. As the population of persons age 50 years and older swells to 112.5 million by 2020, the nonmedical use of psychotherapeutics will increase by 190% (to 2.7 million) by the same year. This will be reflected by a doubling of the current rate (1.2% rising to 2.4%).53
Unfortunately, few data exist regarding the epidemiology of drug abuse/addiction in the older population and how to detect/prevent it. Few healthcare professionals feel equipped to identify drug abuse. Less than 40% of physicians have received training in prescription drug abuse, and only 50% of pharmacists have received such training since graduation.53
Unfortunately, the DDI evidence base for the opioid analgesics is substantially underdeveloped. The elderly and chronic pain populations have been grossly underrepresented herein. Most data have been presented in case reports or case series, while in the case of methadone, most data have originated in 20-60-year-old inpatients receiving MMT at doses below 200 mg daily. Data derived from MMT patients may not be easily extrapolated to those with chronic pain and/or elderly persons due to the unique aspects of this patient population: frequent co-infection with human immunodeficiency virus (HIV) and, hence, the need to co-administer antiretrovirals; other potential interacting agents, such as cocaine, tobacco, and marijuana, are frequently co-ingested; and opioid pharmacokinetics can be altered in these patients (eg, increased volume of distribution and changes in plasma protein binding as compared to non-MMT subjects).55
In July 2005, a potentially lethal DDI led to the withdrawal of ER hydromorphone hydrochloride from the marketplace. This DDI was characterized by dangerously rapid drug release from the formulation (“dose-dumping”). In an unpublished study conducted by the manufacturer in 24 healthy volunteers in fed and fasting states, co-administration of 12 mg of ER hydromorphone with 240 mL of 40% ethanol in water produced a mean sixfold increase in peak plasma concentrations (Cmax); (one subject had a 16-fold increase). Even when the ethanol dose was reduced to an amount equivalent to that found in two-thirds of a usual serving of beer, the Cmax still rose a mean of twofold. This interaction was more pronounced in the fasting versus fed state.56 Recently, the manufacturer of a morphine sulfate ER formulation (Actavis US, Morristown, NJ) evaluated its interaction with ethanol; 240 mL of 40% ethanol in water alone or after a standard high-fat test meal had no significant effect on the pharmacokinetics of morphine. The 90% CIs for area under the plasma concentration-versus-time curve (AUC) and Cmax fell entirely within the 80-125% bioequivalence criterion ranges.57
Table III illustrates clinically relevant pharmacokinetic and pharmacodynamic DDIs between opioid analgesics and other drugs.55,58-60 It is clear that methadone is the opioid most clearly affected by DDIs. Interactions that cause a fall in serum opioid concentrations can reduce the analgesic effect and precipitate an opioid withdrawal reaction. Interactions that cause serum opioid concentrations to rise can enhance drug toxicity.
One of the AEs precipitated by serum drug concentration elevations is cardiotoxicity associated with methadone. Although occasionally manifesting as bradycardia, the most clinically important toxic reaction is prolongation of the QTc interval, predisposing to polymorphous ventricular tachycardia (Torsades de pointes), and then to ventricular fibrillation and death. The major risk factors for methadone cardiotoxicity include concurrent use of other medications that prolong the QTc interval or inhibit the metabolism of methadone, electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia), and pre-existing structural cardiac disease. Recommendations to improve the cardiac safety of methadone have recently been published.61-63
Multiple combination products of aspirin, ibuprofen, or acetaminophen with opioids such as codeine, oxycodone, or hydrocodone are available. One disadvantage of such products is the inability to individually adjust the dose of each component to optimize therapy. Frequently, the opioid dose is limited by the safe dosage limits of the nonopioid component. For example, salicylism is possible when aspirin ingestion from the combination exceeds 4 g per day. Acetaminophen daily doses should not exceed 4 g per day (less in patients with a history of liver disease, alcoholism, or co-ingesting drugs that are potent hepatic enzyme inducers). Another disadvantage is the nature of the nonopioid component itself. NSAIDs such as aspirin and ibuprofen may cause gastropathy (peptic ulcers, esophagitis) and renal failure, and should seldom be used chronically as analgesics in the elderly. A final disadvantage is the difficulty in assessing the quantity of the nonopioid component being ingested by the patient in products other than the combination product itself. With the ubiquitous availability of all three nonopioids in scores of over-the-counter and complementary and alternative medicine products, the importance of a thorough medication history becomes evident. However, since most patients do not consider the latter two drug classes to really be “drugs,” securing a thorough history of all drugs ingested can be a challenge. The only circumstance in which a combination product might be useful is when the individually adjusted and optimized components can be supplied exactly (in terms of drug components and dosage strengths) by an existing combination product. In this case, there can be a reduction in dosage units ingested per day and, frequently, reduction in the cost as well.
The author reports no relevant financial relationships.
Dr. Guay is Professor of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, and Consultant, HealthPartners Inc., Minneapolis.
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